Edited by: Qi Fu, The Institute for Exercise and Environmental Medicine and UT Southwestern Medical Center, USA
Reviewed by: Julian Mark Stewart, New York Medical College, USA; David Andrew Low, Liverpool John Moores University, UK
*Correspondence: Satish R. Raj, AA3228 Medical Center North, Vanderbilt University, 1161 21st Avenue South, Nashville, TN 37232-2195, USA e-mail:
This article was submitted to Integrative Physiology, a section of the journal Frontiers in Physiology.
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The Postural Tachycardia Syndrome (POTS) is the most common disorder seen in autonomic clinics. Cardinal hemodynamic feature of this chronic and debilitating disorder of orthostatic tolerance is an exaggerated orthostatic tachycardia (≥30 bpm increase in HR with standing) in the absence of orthostatic hypotension. There are multiple pathophysiological mechanisms that underlie POTS. Some patients with POTS have evidence of elevated sympathoneural tone. This hyperadrenergic state is likely a driver of the excessive orthostatic tachycardia. Another common pathophysiological mechanism in POTS is a hypovolemic state. Many POTS patients with a hypovolemic state have been found to have a perturbed renin-angiotensin-aldosterone profile. These include inappropriately low plasma renin activity and aldosterone levels with resultant inadequate renal sodium retention. Some POTS patients have also been found to have elevated plasma angiotensin II (Ang-II) levels, with some studies suggesting problems with decreased angiotensin converting enzyme 2 activity and decreased Ang-II degradation. An understanding of these pathophysiological mechanisms in POTS may lead to more rational treatment approaches that derive from these pathophysiological mechanisms.
Postural Tachycardia Syndrome (POTS) is a debilitating syndrome that is characterized by symptoms of presyncope when assuming an upright position. This syndrome is the most common disorder seen in autonomic specialty clinics and affects 500,000–3,000,000 individuals in the United States (Robertson,
Neurohormonal dysregulation has been identified in a number of patients with POTS. We will discuss the data supporting this implication and review the neurologic and hormonal aspects of POTS as it pertains to the pathophysiology of this condition.
POTS is a heterogeneous syndrome with several different pathophysiological mechanisms that can result in the typical POTS presentation, and a few more common ones are highlighted in this manuscript (Figure
Partial autonomic neuropathy | Partial autonomic neuropathy in lower extremities | Midodrine (Jacob et al., |
An alpha-1 agonist that increases peripheral vasoconstriction |
Abnormal splanchnic blood flow and pooling | Octreotide (Hoeldtke and Davis, |
A somatostatin analog that decreases splanchnic blood flow | |
Perturbed renin-angiotensin aldosterone system and hypovolemia | Inappropriately low levels of renin and/or aldosterone | Exercise (Fu et al., |
Precise mechanism unclear, but increases renin:aldosterone ratio |
Low blood and/or plasma volume | Exercise (Fu et al., |
Increases plasma volume | |
Fludrocortisone (Freitas et al., |
A mineralocorticoid that increases sodium and water retention | ||
Erythropoietin (Hoeldtke et al., |
A hormone that increases blood volume | ||
Saline Infusions (Jacob et al., |
Acutely increases plasma volume | ||
DDAVP (Coffin et al., |
An ADH analog that increases intravascular volume | ||
Hyperadrenergic State | Increased secretion and clearance of norepinephrine | Propranolol (Raj et al., |
A non-selective beta-blocker that impairs sympathetic activation |
Pyridostigmine (Raj et al., |
An acetylcholinesterase inhibitor that increases parasympathetic activity and slows heart rate |
In 1988, Streeten et al. first published a report regarding the pathophysiology of POTS. In 34 patients with symptoms of orthostatic intolerance, 10 patients exhibited orthostatic increases in HR >30 bpm. In these 10 individuals, radioisotopic measurements of orthostatic pooling of blood in the calf was significantly greater compared to healthy subjects (
Stewart and Weldon confirmed increases in orthostatic leg volume and venous blood flow consistent with excessive pooling in the lower extremities in a pediatric POTS population using strain-gauge measurements (Stewart and Weldon,
Both Doppler ultrasound and segmental impedance plethysmography (Diedrich and Biaggioni,
An explanation for this adverse blood pooling is a partial autonomic neuropathy. Schondorf and Low initially found evidence of generalized autonomic neuropathy in patients with POTS (Schondorf and Low,
In more recent years, hormonal research as it relates to the pathophysiology of POTS has converged on the renin-angiotensin aldosterone system. Low blood volume (red cell volume and plasma volume) has been demonstrated in multiple studies in POTS patients (Jacob et al.,
Subsequent work has also shown that plasma Ang-II levels in some POTS patients are elevated when compared to healthy subjects (Stewart et al.,
Ang-II exerts most of its physiologic effects though AT1R (De Gasparo et al.,
Medow et al. found that there was defective cutaneous vasodilation of the microvasculature mediated by nitric oxide with local heating in POTS patients versus healthy subjects (Medow et al.,
ACE2 is a monocarboxypeptidase that metabolizes Ang-II, an octapeptide, into Angiotensin 1-7 [Ang(1-7)]. Ang(1-7) has vasodilatory properties and has actions that generally oppose that of Ang-II (Chappell,
Stewart et al., showed that with local infusion of losartan and a NOS inhibitor, cutaneous vasodilation due to local heating is reduced in healthy subjects to the level of POTS patients (Stewart et al.,
Mustafa et al. also showed that this deficiency in ACE2 extends into the systemic circulation by measuring the ratio of Ang(1-7) to Ang-II and used it as a surrogate for functional ACE2 activity (Mustafa et al.,
The source of ACE2 dysfunction in POTS patients is still unclear. A specific genetic mutation could be the cause. Alternatively, ACE2 dysfunction could be a downstream manifestation resulting from POTS. As most POTS patients are intolerant of physical activity, ACE2 dysfunction could be a product of general deconditioning. Prior research has shown that diet, at least in the short term, does not affect level of ACE2 activity (Mustafa et al.,
Another possibility is that the measured Ang-II might not really be Ang-II. Most prior studies that have quantified Ang-II have employed assays that were not sensitive enough to distinguish Ang-II from angiotensin 3 or angiotensin 4 since they typically employed radioimmunoassays that targeted the peptides common to the C-terminus (Stewart et al.,
The exact mechanism of how a defect in ACE2 might trigger the clinical manifestations of POTS is also still poorly understood. While there may be a deficiency in peripheral and cutaneous vasodilation secondary to an ACE2 defect, it is not clear how that produces orthostatic tachycardia and presyncopal symptoms.
In addition to the “renin-aldosterone paradox” with the lack of aldosterone response in the presence of hypovolemia, the high Ang-II levels and low ACE2 activity remains to be explained.
Previous studies in normal healthy subjects have demonstrated normal supine plasma norepinephrine levels to be around 200 pg/mL (Jacob et al.,
Using muscle sympathetic nerve activity (MSNA) as measured by microneurography, sympathetic nervous activity (SNA) in POTS patients has been shown to differ from that of healthy subjects at rest (Furlan et al.,
One etiology behind this exaggerated SNA response is attributed to norepinephrine transporter (NET) dysfunction. Administration of a NET inhibitor, reboxetine, to healthy subjects has been shown to produce a POTS phenotype with increase of HR in response to head-up tilt testing by greater than 30 bpm (Schroeder et al.,
This hyperadrenergic state can be “secondary” such as in response to hypovolemia, or “primary” such as one related to a genetic mutation. Shannon et al. demonstrated that a specific genetic mutation can cause POTS. A specific missense mutation in the exon of the norepinephrine transporter gene (
There is also some data that the parasympathetic system may contribute to the tachycardia in POTS. Furlan et al. reported that high frequency R-R interval variability (0.15–0.4 Hz), a marker of parasympathetic activity, was reduced in POTS patients compared to healthy subjects during passive orthostatism (Furlan et al.,
Alpha-1 agonists have been used in POTS patients to restore the lack of adrenergic vasoconstriction due to partial autonomic neuropathy in the lower extremities. Phenylephrine infusions have previously been shown to improve HR and enhance peripheral vasoconstriction in POTS patients. However, phenylephrine infusion also increased BP in these patients (Stewart et al.,
Octreotide is a somatostatin analog that causes vasoconstriction in the splanchnic vascular bed. It has been shown to significantly reduce orthostatic tachycardia in POTS patients to a similar extent that midodrine does (Hoeldtke and Davis,
Fludrocortisone is a potent fluorinated aldosterone agonist that causes significant sodium and water retention (Thorn et al.,
Desmopressin (DDAVP) is an orally available synthetic analog of arginine vasopressin. In a study of 30 POTS patients, the short-term administration of DDAVP orally reduced the degree of orthostatic tachycardia compared to placebo significantly (
Erythropoietin has also been used to treat the decreased blood volume in POTS patients by artificially increasing erythropoiesis. Hoeldtke et al. initially found no improvement in reducing orthostatic tachycardia in a small study involving 8 patients with orthostatic intolerance after 6–12 weeks of erythropoietin treatment. Furthermore, supine as well as standing BP were elevated (Hoeldtke et al.,
The use of volume loading with intravenous saline is effective at acutely relieving the symptoms of POTS. Jacob et al. showed that the infusion of 1 liter of normal saline over a time period of 1 h was effective in significantly reducing orthostatic tachycardia at 1 h upon the completion of the infusion (Jacob et al.,
Fu et al. conducted a trial before-after exercise training to 3 months of an exercise regimen consisting of 4 sessions per week, each lasting 30–45 min (
Attempts to manage the hyperadrenergic state in these individuals center around HR control. The use of beta-blockade to decrease HR has been met with conflicting data. Masuki et al. had previously shown that POTS patients had reduced stroke volumes and required a faster upright HR to maintain cardiac output (Masuki et al.,
Pyridostigmine, an acetylcholinesterase inhibitor, has also been used to manage orthostatic tachycardia (Raj,
Given that a defective norepinephrine transporter has been implicated in causing hyperadrenergic POTS, medications that inhibit norepinephrine reuptake worsen tachycardia in POTS patients (Shannon et al.,
Over the past 20 years, considerable research has taken place in an effort to understand and explain this enigmatic syndrome. Several neural and hormonal observations have been made in regard to the pathophysiology of POTS. POTS patients have variously been shown to have a partial neuropathic state with impaired lower extremity sympathetic innervations, abnormal venous pooling, a hypovolemic state with inadequate RAAS upregulation, cutaneous blood flow dysregulation, and also increased plasma Ang-II levels. In recent years, pathophysiology research for POTS has shifted toward work on the RAAS, and considerable emphasis has been placed on the Ang-II/ACE2/Ang(1-7) axis (Stewart et al.,
As the etiology of POTS is not completely understood, it is unclear if the Ang-II/ACE2/Ang(1-7) axis is the unifying pathologic mechanism that drives the pathophysiology for all the manifestations of POTS that do not as of yet have a crystal-clear explanation. Alternatively, the manifestations for each variant may simply be one of several but typical downstream responses to a defective Ang-II/ACE2/Ang(1-7) axis or another unifying pathologic mechanism. If so, then the exact steps that link these manifestations to that unifying pathologic mechanism will need to be elucidated.
Supported in part by NIH grants R01 HL102387, P01 HL56693, and UL1 RR024975 (Clinical and Translational Science Award).
National Institutes of Health grants R01 HL102387, P01 HL56693, and UL1 RR024975 (Clinical and Translational Science Award). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.